Protein aggregation is considered a key pathophysiological feature of many neurodegenerative diseases including Parkinson's disease (PD). The progressive accumulation of alpha-synuclein protein aggregation has been implicated in the progression of disease severity of PD; however, the biological mechanisms underlying the propagation of these diseases are not well understood. Environmental exposure to manganese has been linked to Parkinson's like neurological conditions in humans. The concept that 1-synuclein protein aggregates spread via a prion-like mechanism has emerged in the last two years. Prion and 1-synuclein proteins share some common structural features including multiple divalent metals binding sites that can bind to metals like copper and manganese (Mn) and a GAV consensus motif that plays a role in fibrillization and neurotoxicity. Recently, the investigators observed that manganese exposure stabilizes cellular prion by binding to the metal binding sites contributing to neurotoxicity. While investigating the effect of manganese on prion protein, the investigators unexpectedly found that Mn treatment also upregulates 1-synuclein neuronal cells, suggesting that metal binding to prion and 1-synuclein may promote pathological interactions that contribute to the disease progression. Thus, the recent discovery that 1-synuclein protein aggregation in PD is similar to prion pathology and the established role of environmental manganese exposure in Parkinsonian-like conditions have lead to a novel hypothesis that the divalent metal manganese interacts with 1-synuclein and prion proteins to promote prion-like propagation of protein aggregation, which contributes to the progression of neurodegenerative processes. A transdisciplinary research team comprised of a biophysicist, a neurobiologist, and a neurotoxicologist will use the ViCTER funding mechanism to test this novel hypothesis using detailed investigations from the molecular level to the system level. The specific aims to be addressed in the proposal are: i) to determine at the single molecule level if exposure to manganese increases the homophilic aggregation and heterophilic cross-talk between prion proteins and 1-synuclein, ii) to determine the reciprocal neuropathological interactions between manganese exposure and 1-synuclein and prion protein accumulation, and iii) to determine whether manganese interacts with 1-synuclein protein to accelerate the prion like aggregation of the protein in order to augment neuronal degeneration. This collaborative research project is unique and will provide new insights into the role of divalent metals in the prion-like disease progression of chronic neurodegenerative processes in PD. PUBLIC HEALTH RELEVANCE: Although protein aggregation is considered a hallmark of various neurodegenerative disorders, the effect of environmental neurotoxic metals on protein aggregation processes is not well characterized. This application aims to characterize the effect of manganese on aggregation of a key cellular protein associated with Parkinson's disease, namely 1-synuclein, and to define the potential interaction of 1- synuclein with prion protein with respect to the propagation of protein aggregation and neurotoxicity. The results of this collaborative project will provide new insights into the role of divalent metals in the progression of neurodegenerative processes in environmentally linked Parkinson's disease.